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Transforming Growth Factor-ß Promotes Survival of Mammary Carcinoma Cells through Induction of Antiapoptotic Transcription Factor DEC1

¹ Department of Biochemistry, Cancer Institute of the Japanese Foundation for Cancer Research; ² Department of Urology, Graduate School of Medicine, Juntendo University; ³ Department of Molecular Pathology, Graduate School of Medicine and ⁴ Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan and ⁵ Department of Dental and Medical Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

Requests for reprints: Kohei Miyazono, Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-3-5841-3345; Fax: 81-3-5841-3354; E-mail: miyazono-ind{at}umin.ac.jp.

Transforming growth factor-ß (TGF-ß) signaling facilitates tumor growth and metastasis in advanced cancer. In the present study, we identified differentially expressed in chondrocytes 1 (DEC1, also known as SHARP2 and Stra13) as a downstream target of TGF-ß signaling, which promotes the survival of breast cancer cells. In the mouse mammary carcinoma cell lines JygMC(A) and 4T1, the TGF-ß type I receptor kinase inhibitors A-44-03 and SB431542 induced apoptosis of cells under serum-free conditions. Oligonucleotide microarray and real-time reverse transcription-PCR analyses revealed that TGF-ß induced DEC1 in these cells, and the increase of DEC1 was suppressed by the TGF-ß type I receptor kinase inhibitors as well as by expression of dominant-negative TGF-ß type II receptor. Overexpression of DEC1 prevented the apoptosis of JygMC(A) cells induced by A-44-03, and knockdown of endogenous DEC1 abrogated TGF-ß–promoted cell survival. Moreover, a dominant-negative mutant of DEC1 prevented lung and liver metastasis of JygMC(A) cells in vivo. Our observations thus provide new insights into the molecular mechanisms governing TGF-ß–mediated cell survival and metastasis of cancer. [Cancer Res 2007;67(20):9694–703]